1. Field of the Invention
The present invention relates to novel benzothiepines, derivatives and analogs thereof, in combination with HMG Coxe2x80x94A reductase inhibitors, pharmaceutical compositions containing them, and use of these compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia is mammals.
2. Description of the Related Art
It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol is a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, in xe2x80x9cInteraction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,xe2x80x9d Biochimica et Biophysica Acta. 1210 (1994) 255-287 discusses the biochemistry, physiology and known active agents surrounding bile acids and cholesterol.
Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, J. E., et al. See xe2x80x9cPrimary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transportxe2x80x9d, Gastroenterology, 1982:83:804-11.
In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihnxc3xa9r E. et al, in xe2x80x9cRegulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMGxe2x80x94CoA reductase activity and low density lipoprotein receptor expression in gallstone patientsxe2x80x9d, Journal of Lipid Research, Volume 31, 1998, 2219-2225 and Suckling et al, xe2x80x9cCholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatmentxe2x80x9d, Atherosclerosis, 89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation or the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.
In another approach to the reduction or recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption or the enterohepatic circulation with specific transport inhibitors (Kramer, et al, xe2x80x9cIntestinal Bile Acid Absorptionxe2x80x9d The Journal of Biological Chemistry, Vol. 268, No. 24, Issue of Aug. 25, pp. 18035-18046, 1993).
In a series of patent applications, eg Canadian latent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and; in particular for use as hypocholesterolemic agents.
In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure or the world patent application number WO 93/16055 for xe2x80x9cHypolipidemic Benzothiazepine Compoundsxe2x80x9d
Selected benzothiepines are disclosed in world patent application number WO 93/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.
Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolemic agents, especially for the treatment of prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring.
The above references show continuing efforts to find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.
Additionally selected benzothiepines are disclosed for use in various disease states not within the present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO 89/1477/A as abstracted in Derwent Abstract No. 89-370688; U.S. Pat. No. 3,520,891 abstracted in Derwent 50701R-B; U.S. Pat. No. 3,287,370, U.S. Pat. No. 3,389,144; U.S. Pat. No. 3,694,046 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.
HMG Coxe2x80x94A reductase inhibitors have been used as cholesterol-lowering agents. This class of compounds inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG Coxe2x80x94A) reductase. This enzyme catalyzes the conversion of HMG Coxe2x80x94A to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.
Benzothiazepine anti-hyperlipidemic agents are disclosed in WO 94/18183, WO 94/18184, WO 96/05188, WO 96/16051, AU-A-30209/92, AU-A-61946/94, AU-A-61948/94, and AU-A-61949/94.
The present invention furthers such efforts by providing novel pharmaceutical compositions and methods for the treatment of hyperlipidemic conditions.
Accordingly, among its various aspects, the present invention provides compounds of formula (I): 
wherein:
q is an integer from 1 to 4;
n is an integer from 0 to 2;
R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkenyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,
wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl optionally are e substituted with one or more substituents selected from the group consisting of OR9, NR9R10, Nxe2x88x92NR9NR10RWAxe2x88x92, SR9, S+R9R10Axe2x88x92, Pxe2x88x92R9R10R11Axe2x88x92, S(O)R9, SO2R9, SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10,
wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one oz more carbons replaced by O, NR9, N+NR9R10Axe2x80x94, S, SO, SO2, S+R9Axe2x80x94, P30NR9R10Axe2x80x94, or phenylene,
wherein R9, R10, and RW are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or
R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkylidene;
R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, heteroaryl, OR9, NR9R10, SR9, S(O)R9, SO2R9, and SO3R9, wherein Rxe2x80x2 and R10are as defined above; or
R3 and R4 together form xe2x95x90O, xe2x95x90NOR11, xe2x95x90S, xe2x95x90NMR11R12, xe2x95x90NR9, or xe2x95x90CR11R12,
wherein R11and R12 are independently selected from the group consisting of H, alkyl, alkenyl. alkenyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, heteroaryl carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cycloalkyl, OR9, NR9R10, SR9, S(O)R9, SO2R9, SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10,
wherein R9and R10are as defined above provided that both R3 and R4 cannot be OH, NH2 and SH, or
R11and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkenyl, aryl, cycloalkyl, heterocycle, heteroaryl; quaternary heterocycle, quaternary heteroaryl SR9, A(O)R9, SO2R9,l and SO3R9,
wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR14, NR13NR14NR15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15Axe2x80x94, P(OR13)OR14, Sxe2x88x92R13R14Axe2x88x92, and N+NR9R11R12Axe2x88x92,
wherein:
Axe2x88x92 is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation,
said alkyl , alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S(O)R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N+R7R8R9Axe2x80x94, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R7R8, P+R7R8R9Axe2x88x92, and P(O) (OR7) OR8, and
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by O, NR7, N+R7R8Axe2x80x94, S, SO, SO2, S+R7Axe2x80x94, PR7, P(O)R7, P+R7R8Axe2x80x94, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl,
wherein, alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl, and polyalkyl optionally have one or more carbons replaced by O, NRxe2x80x2, N+R9R10Axe2x80x94, S, SO, SO2, S+R9Axe2x88x92, PR9, P30R9R10Axe2x80x94, P(O)R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and
R13, R14, and R15are optionally substituted with one or none groups selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N+NR9R11R12Axe2x88x92, SR9, S(O)R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO(OR16)OR17, P30R9NR10R11Axe2x80x94, S+R9R10Axe2x80x94, and C(O))M,
wherein R16 and R17, are independently selected from the substituents constituting R9 and M; or
R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring;
R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and
one or more RX are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S(O)R13, S(O)R13, SO3R13, S+R13R14Axe2x80x94, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, NR14C(O)R13, C(O)NR13R14, NR14C(O)R13, C(O)OM, COR13, OR18, S(O)nNR18, NR13R18, NR18OR14, N+NR9R11R12Axe2x88x92, P+R9R11R12Axe2x88x92, amino acid, peptide, polypeptide, and carbohydrate,
wherein alkyl, alkenyl, are alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N+NR9R11R12Axe2x88x92, SR9, S(O)R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO(OR16) OR17, P+R9R11R12Axe2x88x92, Sxe2x88x92R9R10Axe2x88x92, or C(O)OM, and
wherein R18is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl
wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N+R9R11R12Axe2x88x92, SR9, S(O)R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO3R9, SO2OM, SO2NR9R10, PO(OR16)OR17, and C(O)OM,
wherein in RX, one or more carbons are optionally replaced by O, NR13, N+R13R14Axe2x80x94, S, SO, SO2, S+R13Axe2x80x94, PR13, P(O)R13P+R13R14Axe2x80x94, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,
wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR9, N+R9R10Axe2x80x94, S, SO, SO2, S+R9Axe2x80x94, PR9, P+R9R10Axe2x80x94,
wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkenyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15Axe2x80x94, P(OR13) OR14, Sxe2x88x92SR13R14Axe2x88x92, and N+NR9R11R12 ,A31,
provided that both R5 and R6 cannot be hydrogen, OH, or SH, and when R5 is OH, R1, R2, R3, R4, R7, and R8 cannot be all hydrogen;
provided that when R5 or R4 is phenyl, only one of R1 or R2 is H;
provided that when q=1 and R6 is styryl, anilido, or anilinocarbonyl, only one of R5 or R6 is alkyl; or
a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Preferably, R5 and R6 can independently be selected from the group consisting of H, aryl, heterocycle, heteroaryl, quaternary heterocycle, and quanternary heteroaryl,
wherein said aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituted groups independently selected from the group consisting of alkyl, alkenyl, alkenyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2NR13R14, C(O)NR13R14, C(O)OM COR13, P(O)R13R14, P+R13R14R15Axe2x80x94, P(OR13)OR14, S+R13R14Axe2x80x94, and N+NR9R11R12Axe2x88x92,
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one of more carbons replaced by O, NR7, N+R7R8Axe2x80x94, SO, SO2, S+R7Axe2x80x94, PR7, P(O)R7 P+R7R8Axe2x80x94, or phenylene
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S(O)R7, SO3R7, CO2R7, CN, oxo, CONR7R8, Nxe2x88x92R7R8R9Axe2x80x94, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R7R8, P+R7R8R9Axe2x80x94, and P(O)(OR7)OR8.
More preferably R5 or R6 has the formula:
xe2x80x94Arxe2x80x94(Ry)t
wherein:
t is an integer from 0 to 5;
Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazoly, benzothiazolyl, and benzoisothiazolyl; and
one or more Ry are independently selected from the group consisting of H, alkyl, alkenyl, alkenyl, aryl, cycloalkyl, heterocycle, heteroaryl: quaternary heterocycle, quaternary heteroaryl OR9, SR9, S(O)R9, SO2R9,l and SO3R9,
wherein alkyl, alkenyl, alkenyl, aryl, cycloalkyl, heterocycle, and heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkenyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15Axe2x80x94, P(OR13)OR14, Sxe2x88x92R13R14Axe2x88x92, and N+R9R11R12Axe2x88x92,
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S(O)R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N+R7R8R9Axe2x80x94, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl P(O)R7R8, P+R7R8R9Axe2x80x94, and P(O)(OR7)OR8, and
wherein said alkyl, alkenyl, alkenyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one of more carbons replaced by O, NR7, N+R7R8Axe2x80x94, S, SO, SO2, S+R7Axe2x80x94, PR7, P(O)R7, P+R7R8Axe2x80x94, or phenylene.
Most preferably, R5 or R6 has the formula (II): 
The invention is further directed to a compound selected from among: 
wherein R19is selected from the group consisting of alkane diyl, alkane diyl, alkane diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon atoms replaced by O, NR7, N+R7R8, S, SO, SO2, S+R7R8, PR7, P+P7R8, phenylene, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, or aryl,
wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkenyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, R13R14R15Axe2x80x94, P(OR13)OR14, Sxe2x88x92R13R14Axe2x88x92, and N+R9R11R12Axe2x88x92;
wherein R19 further comprises functional linkages by which R19 is bonded to R20, R21, or R22 in the compounds of Formulae DII and DIII, and R23 in the compounds of Formula DIII. Each of R20, R21, or R22and R23comprises a benzothiepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.
The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DIII in which each of R20, R21, R22and R23 comprises a benzothiepine moiety corresponding to the Formula: 
wherein R1, R2, R3, R4, R5, R6, R7, R8, Rx, q and n are as defined in Formula I as described above, and R55 is either a covalent bond or arylene.
In compounds of Formula DIV, it is particularly preferred that each of R20, R21, and R22 in Formula DII and DIII, and R23 in Formula DIII, be bonded at its 7-or 8-position to R19. In compounds of Formula DIVA it is particularly preferred that R55 comprise a phenylene moiety bonded at a m- of p-carbon thereof to R19.
Examples of Formula DI include: 
In any of the dimeric or multimeric structures discussed immediately above, benzothiepine compounds of the present invention can be used alone or in various combinations.
In any of the compounds of the present invention, R1 and R2 can be ethyl/butyl or butyl/butyl,
Other compounds useful in the present invention as ileal bile acid transport inhibitors are shown in Appendix A.
In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a disease or condition for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis. Such compositions comprise any of the compounds disclosed above, alone or in combination in an amount effective to reduce bile acid levels is in the blood, or to reduce transport thereof across digestive system membranes, and a pharmaceutically acceptable carrier, excipient, or diluent.
In a further aspect, the present invention also provides a method of treating a disease or condition in mammals including humans for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses.
In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention.
In yet another aspect, the present invention provides a combination therapy comprising the use of a first amount of an ileal bile acid transport inhibitor and a second amount of a HMG Coxe2x80x94A reductase inhibitor useful to treat hyperlipidemic disorders, wherein said first and second amounts together comprise an anti-hyperlipidemic condition effective amount of said compounds.
HMG Coxe2x80x94A reductase inhibitor-compounds useful in the present invention are shown in Appendix B.
Further scope of the applicability of the present invention will became apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.